Phase I trial of paclitaxel and gemcitabine administered every two weeks in patients with refractory solid tumors

Purpose. Paclitaxel and gemcitabine possess broad spectra of clinical activity, distinct mechanisms of cytotoxicity, and are differentially affected by mutations in cell-cycle regulatory proteins, such as bcl-2. This phase I trial was designed to identify the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of paclitaxel and gemcitabine when both drugs were given together on a once-every-two-week schedule in patients with solid tumors. Patients and methods. A total of 37 patients were treated at nine different dose levels ranging from paclitaxel 75-175 mg/m(2) administered over three hours followed by gemcitabine 1500-3500 mg/m(2) administered over 30-60 minutes. Both drugs were administered on day 1 of a 14-day cycle. Dose escalation was performed in a stepwise manner in which the dose of one drug was escalated while the dose of the other drug was kept constant. Results: Dose limiting toxicity (DLT) was observed at dose level 9: paclitaxel 175 mg/m(2) and gemcitabine 3500 mg/m(2) in the form of grade 4 neutropenia lasting for greater than or equal to 5 days (one patient) and grade 3 elevation of alanine aminotransferase (AST/SGPT) (one patient). An analysis of delivered dose intensity (DI) over the first three cycles revealed that higher dosages of both drugs were delivered at dose level 7, paclitaxel 150 mg/m(2) and gemcitabine 3000 mg/m(2) dose level, than at the MTD, dose level 8, paclitaxel 150 mg/m(2) and gemcitabine 3500 mg/m(2). Partial responses were confirmed in two patients with transitional cell carcinoma (one of the bladder, one of the renal pelvis) and in one patient with adenocarcinoma of unknown primary. Conclusions: Paclitaxel and gemcitabine is a promising drug combination that can be administered safely and repetitively on an every-other-week schedule. Using this drug administration schedule, the recommended phase II dose is paclitaxel 150 mg/m(2) and gemcitabine 3000 mg/mg(2).